Base Excision Repair Gene Polymorphisms Research Articles

Interaction of base excision repair gene polymorphism and estrogen-DNA adducts in breast cancer risk among East Asian women.

In East Asia, the incidence of breast cancer has been increasing rapidly, particularly among premenopausal women. An elevated ratio of estrogen-DNA adducts was linked to a higher risk of breast cancer. The present study explored the influence of the interaction between base excision repair (BER) gene polymorphisms and estrogen-DNA adducts on breast cancer risk. We conducted a case-control study comprising healthy volunteers and individuals with benign breast disease (control arm, n = 176) and patients with invasive carcinoma or carcinoma in situ (case arm, n = 177). Genotyping for BER-related genes, including SMUG1, OGG1, ERCC5, and APEX1, was performed. A logistic regression model, incorporating interactions between gene polymorphisms, estrogen-DNA adduct ratio, and clinical variables, was used to identify the risk factors for breast cancer. Univariate analysis indicated marginal associations between breast cancer risk and APEX1 rs1130409 T > G (P = 0.057) and APEX1 rs1760944 T > G (P = 0.065). Multivariate regression analysis revealed significant associations with increased breast cancer risk for APEX1_rs1130409 (GT/GG versus TT) combined with a natural logarithmic value of the estrogen-DNA adduct ratio (estimated OR 1.164, P = 0.023) and premenopausal status with an estrogen-DNA adduct ratio > 2.93 (estimated OR 2.433, P = 0.001). APEX1_rs1130409 (GT/GG versus TT) polymorphisms, which are related to decreased BER activity, combined with an increased ratio of estrogen-DNA adducts, increase the risk of breast cancer in East Asian women.

Single Nucleotide Polymorphisms (SNPs) of OGG1 (Ser326Cys) and APE1 (Asp148Glu; –141T/G) Genes and Breast Cancer Risk in Filipino Women

Base excision repair (BER) pathway involves repair of damaged DNA caused by spontaneous decay of DNA, reactive oxygen species, and ionizing radiation. Polymorphisms of genes involved in the pathway have been reported to be associated with cancer risk. In this study, the association of BER gene polymorphisms with breast cancer risk in Filipino women was assessed. The polymorphisms studied included X-ray repair cross-complementing group 1 (XRCC1, Arg399Gln), 8-oxoguanine DNA glycosylase (OGG1, Ser326Cys), and apurinic/apyrimidinic endonuclease 1 (APE1, Asp148Glu; –141T/G). A total of 186 participants (93 breast cancer cases and 93 breast cancer-free control) were recruited for the study. The genotyping of samples was performed using polymerase chain reaction with confronting two-pair primers (PCR-CTPP). The association of polymorphisms of BER genes with breast cancer risk and gene-environment interaction was determined using the unconditional logistic regression model. Distributions of OGG1 and APE1 genotypes were in Hardy-Weinberg equilibrium (HWE); however, XRCC1 genotype distribution deviated from HWE and was not further analyzed. The analysis showed that OGG1 Ser326Cys, APE1 Asp148Glu, and APE1 –141T/G had no significant association with breast cancer risk. Also, there is no significant interaction between the three BER gene variants and family history of cancer. Lastly, no significant increased risk was observed when the combined effects of risk alleles of the three BER gene variants were determined. In conclusion, the study suggests that OGG1 Ser326Cys, APE1 Asp148Glu, and APE1 –141T/G are not good indicators of breast cancer risk in Filipino women.

Radio-adaptive response, individual radio-sensitivity and correlation of base excision repair gene polymorphism (hOGG1, APE1, XRCC1, and LIGASE1) in human peripheral blood mononuclear cells exposed to gamma radiation.

Radio-adaptive response (RAR) is a biological mechanism, where cells primed with a low dose exhibit reduced DNA damage with a high challenging dose. Single nucleotide polymorphisms (SNPs) of DNA repair genes including base excision repair (BER) pathway are known to be associated with radio-sensitivity but involvement in RAR is not yet understood. In the present study, attempt was made to correlate genotype frequencies of four BER SNPs [hOGG1(Ser326Cys), XRCC1(Arg399Gln), APE1(Asp148Glu) and LIGASE1(A/C)] with DNA damage, repair and mRNA expression level among 20 healthy donors (12 adaptive and 8 nonadaptive). Our results revealed that LIGASE1 (p = .002) showed significant correlation with DNA damage and mRNA expression level with increasing dose. hOGG1 (Ser326Cys), XRCC1 (Arg399Gln) and LIGASE1(A/C) polymorphisms showed significant difference with DNA damage (%T) and mRNA expression profile in primed cells among adaptive donors. In conclusion, BER gene polymorphisms play important role in identifying donors with radio-sensitivity and RAR in human cells.

BER GENE POLYMORPHISMS ASSOCIATED WITH KEY MOLECULAR EVENTS IN BLADDER CANCER

Base excision repair (BER) gene polymorphisms are known to play an independent role in predisposition to developing different cancers as well as to be associated with clinicopathological traits of the disease modifying its clinical outcomes. One of the underlying mechanisms is presumed to include interplay between BER gene polymorphisms and key mutational, epigenetic and chromosomal events in tumor tissues. The present study was aimed at elucidating potential gene-gene interaction and assessing their mutual effects in bladder cancer (BC). The earlier obtained data on genotyping patients with verified diagnosis of BC for OGG1 rs1052133 (Ser326Cys) and XRCC1rs25487 (Arg399Gln) polymorphisms were used for this study. The tumor tissue samples from the same patients were analyzed for mutations, epigenetic variations and losses of heterozygosity in some key genes involved in divergent pathogenic pathways of BC. It was shown that the OGG1(326codon) heterozygous genotype as well as the minor 326Cys allele can intensify a mutational response of the RAS locus in urothelial carcinomas in the total cohort of patients simultaneously decreasing the mutation rates in the PIK3CA locus in smokers. The XRCC1(399codon) heterozygous genotype as well as the minor 399Gln allele reduced the frequency of LOH in the PTEN and TNKS genes, but did not affect the mutational variability in any locus tested. Both polymorphisms influenced the methylation status, carriers of OGG1 326Ser/Cys or Ser/Cys+Cys/Cys genotypes demonstrating increased frequency of methylated RUNX3and ISL1genes whereas the similar effect of XRCC1 polymorphism concerning methylation of p16and TIMP3genes. When dividing the total cohort into groups based on the extent of tumor spread, the observed associations were characteristic of non-muscle invasive BC. The BER gene polymorphisms contributed to modification of key molecular events in urothelial carcinomas. Their mutual effects mainly manifested in non-muscle invasive BC. The underlying mechanisms as well as possible clinical outcomes need to be further explored to propose novel prognostic biomarkers for BC.

P2.01-26 Association of Base Excision Repair Gene Polymorphisms with Response to Chemotherapy of Advanced Non Small-Cell Lung Cancer

P2.01-26 Association of Base Excision Repair Gene Polymorphisms with Response to Chemotherapy of Advanced Non Small-Cell Lung Cancer

Base Excision Repair Gene Polymorphisms and Wilms Tumor Susceptibility

Base excision repair (BER) is the main mechanism to repair endogenous DNA lesions caused by reactive oxygen species. BER deficiency is linked with cancer susceptibility and premature aging. Single nucleotide polymorphisms (SNPs) within BER genes have been implicated in various human malignancies. Nevertheless, a comprehensive investigation of their association with Wilms tumor susceptibility is lacking. In this study, 145 cases and 531 sex and age-matched healthy controls were recruited. We systematically genotyped 18 potentially functional SNPs in six core BER pathway genes, using a candidate SNP approach. Logistic regression was employed to evaluate odds ratio (OR) and 95% confidence interval (CI) adjusted for age and gender. Several SNPs showed protective effects against Wilms tumor. Significant associations with Wilms tumor susceptibility were shown for hOGG1 rs1052133 (dominant: adjusted OR = 0.66, 95% CI = 0.45–0.96, P = .030), FEN1 rs174538 (dominant: adjusted OR = 0.66, 95% CI = 0.45–0.95, P = .027; recessive: adjusted OR = 0.54, 95% CI = 0.32–0.93 P = .027), and FEN1 rs4246215 (dominant: adjusted OR = 0.55, 95% CI = 0.38–0.80, P = .002) polymorphisms. Stratified analysis was performed by age, gender, and clinical stage. Moreover, there was evidence of functional implication of these significant SNPs suggested by online expression quantitative trait locus (eQTL) analysis. Our findings indicate that common SNPs in BER genes modify susceptibility to Wilms tumor.

Polymorphisms of base-excision repair genes and the hepatocarcinogenesis

AimTo determine the possible association between polymorphisms of DNA repair genes, including XRCC1 Arg194Tryp, Arg280His, and Arg399Glu, APE1 Asp148Glu, and NEIL2 Arg257Leu, and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). MethodsA total of 264 subjects were recruited in this retrospective case-control study and were categorized into four groups: 88 control subjects (CR), 53 chronic hepatitis C patients (CHC), 36 liver cirrhotic patients (LC), and 87 HCC patients. The XRCC1 Arg194Tryp, Arg280His, and Arg399Glu polymorphisms were detected using PCR-RFLP, while real-time PCR was used to genotype APE1 Asp148Glu and NEIL2 Arg257Leu. ResultsOur data revealed that, compared with the healthy controls, for those subjects with the XRCC1 Arg194Trp genotype, the risk of developing CHC, LC, and HCC was increased by 6.66- (odds ratio (OR) = 6.667; 95% confidence interval (CI) = 3.244–13.701; P > 0.01), 3.85- (OR = 3.852; 95% CI = 1.797–8.256; P > 0.01), and 2.14-fold (OR = 2.14; 95% CI = 1.13–4.06; P > 0.05), respectively. There was no association between the risk of HCC development and the XRCC1 Arg280His or XRCC1 Arg399Gln genotypes. Moreover, the analysis showed a lack of association between APE1 Asp148Glu and the risk of HCC development. The analysis of clinicopathological parameters showed that the HCC patients with the XRCC1 Arg280His polymorphism were 2.9 fold more likely to have hepatic lesions in both hepatic lobes (OR: 2.9; 95% CI: 1.15–7.29). Notably, in the HCC patients, the prevalence of the APE1 polymorphism in the males was four times higher than that in the females (OR = 4; 95% CI = 1.129–14.175; P > 0.05). ConclusionOur results indicate that the XRCC1 Arg194Trp polymorphism could be a risk factor for HCV-related HCC development in Egypt.

Association of base excision repair gene polymorphisms with response to chemotherapy of advanced non small-cell lung cancer in a Chinese population.

e20504Background: There are significantly differences in the efficacy of platinum based chemotherapy in NSCLC patients. Platinum leads to the cell death by damaging DNA through the chain cross link...

Polymorphisms in BER genes and risk of breast cancer: evidences from 69 studies with 33760 cases and 33252 controls.

Recently, numerous studies have reported an association between single nucleotide polymorphisms in base-excision repair genes and the risk of developing breast cancer, however there is no consensus. The aim of this meta-analysis was to review and quantitatively assess the relationship between single nucleotide polymorphisms in base-excision repair genes and breast cancer risk. The results suggested that a mutation of T to G in rs1760944 may lead to a higher risk of developing breast cancer in the Mongoloid population, and G to A of rs25487 significantly reduced the risk of breast cancer in Mongoloid and Caucasoid populations. In contrast to the CC and CG genotypes, the GG genotype of rs1052133 located on theOGG1 gene appeared to be a protective factor against developing breast cancer in both Mongoloid and Caucasoid populations. There was no evidence to suggest that rs25489, rs1799782, rs1130409, rs1805414 and rs1136410 were associated with breast cancer risk. In conclusion, this study provides evidence to support the theory that DNA repair genes are associated with breast cancer risk, providing information to further understand breast cancer etiology. and The potential biological pathways linking DNA repair, ethnic background, environment and breast cancer require further investigation.

Association of Base Excision Repair Gene Polymorphisms with the Response to Chemotherapy in Advanced Non-Small Cell Lung Cancer.

Background:Base excision repair (BER) plays an important role in the maintenance of genome integrity and anticancer drug resistance. This study aimed to explore the role of BER gene polymorphisms in response to chemotherapy for advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.Methods:During the period from November 2009 to January 2016, a total of 152 patients diagnosed with NSCLC Stage IIIB and IV in the First Hospital of Jilin University were admitted into this study. The XRCC1 G28152A, MUTYH G972C, HOGG1 C1245G, and PARP1 T2444C polymorphisms of all the patients were detected by mass spectrometry. The logistic regression was used for statictical analysis. All tests were bilateral test, and a P < 0.05 was considered statistically significant.Results:The logistic regression model showed that the response rate of chemotherapy of the PARP1 T2444C polymorphisms, CC genotype (odds ratio [OR]: 5.216, 95% confidence interval [CI]: 1.568–17.352, P = 0.007), TC genotype (OR: 2.692, 95% CI: 1.007–7.198, P = 0.048), as well as the genotype of TC together with CC (OR: 3.178, 95% CI: 1.229–8.219, P = 0.017) were significantly higher than those of TT wild type. There was no relationship between the MUTYH G972C, XRCC1 G28152A, and HOGG1 C1245G gene polymorphisms and chemosensitivity.Conclusions:The PARP1 2444 mutation allele C might be associated with the decreased sensitivity to platinum-based chemotherapy in advanced NSCLC. These findings may be helpful in designing individualized cancer treatment.

The impacts of genetic polymorphisms in genes of base excision repair pathway on the efficacy and acute toxicities of (chemo)radiotherapy in patients with nasopharyngeal carcinoma.

PurposeTo explore whether polymorphisms in base excision repair (BER) pathway genes are predictors of (chemo)radiotherapy outcome in patients with nasopharyngeal carcinoma (NPC).MethodsWe genotyped five potentially functional single nucleotide polymorphisms (SNPs) of three genes in the BER pathway in 174 NPC patients who were treated with (chemo)radiotherapy. Sequenom MassArray was used for SNPs analysis. The efficacy at the end of radiotherapy and at 3 months after radiotherapy was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST). Acute radiation toxicity was scored using Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) acute radiation morbidity scoring criteria. Logistic regression was employed to assess the multivariate analyses.ResultsWe found that the wide genotype GG of X-ray repair cross-complementing 1 (XRCC1) rs25489 (GG vs GA: OR=3.833, 95%CI=1.512-9.714, P=0.005; GG vs GA+AA: OR=3.610, 95%CI=1.496-8.713, P=0.004) and the wide genotype CC of 8-oxoguanine DNA glycosylase (OGG1) rs1052133 (CC vs GG: OR=0.263, 95%CI=0.073-0.951, P=0.042; CC vs CG+GG: OR=0.454, 95%CI=0.195-1.053, P=0.066) were positively and negatively associated with primary tumor efficacy at the end of radiotherapy, respectively. By contrast, no association was found between BER gene polymorphisms and the treatment outcomes at 3 months post-treatment or the treatment-related acute toxicities.ConclusionsThe SNPs of the BER genes may act as biomarkers for the curative effect of (chemo)radiotherapy. Further study with long-time follow-up and large population is needed for accurate assessment.

Editor's Highlight: Base Excision Repair Variants and Pesticide Exposure Increase Parkinson's Disease Risk.

Exposure to certain pesticides induces oxidative stress and increases Parkinson's disease (PD) risk. Mitochondrial DNA (mtDNA) damage is found in dopaminergic neurons in idiopathic PD and following pesticide exposure in experimental models thereof. Base excision repair (BER) is the major pathway responsible for repairing oxidative DNA damage in cells. Whether single nucleotide polymorphisms (SNPs) in BER genes alone or in combination with pesticide exposure influence PD risk is unknown. We investigated the contributions of functional SNPs in 2 BER genes (APEX1 and OGG1) and mitochondrial dysfunction- or oxidative stress-related pesticide exposure, including paraquat, to PD risk. We also studied the effect of paraquat on levels of mtDNA damage and mitochondrial bioenergetics. 619 PD patients and 854 population-based controls were analyzed for the 2 SNPs, APEX1 rs1130409 and OGG1 rs1052133. Ambient pesticide exposures were assessed with a geographic information system. Individually, or in combination, the BER SNPs did not influence PD risk. Mitochondrial-inhibiting (OR = 1.79, 95% CI [1.32, 2.42]), oxidative stress-inducing pesticides (OR = 1.61, 95% CI [1.22, 2.11]), and paraquat (OR = 1.54, 95% CI [1.23, 1.93]) were associated with PD. Statistical interactions were detected, including for a genetic risk score based on rs1130409 and rs1052133 and oxidative stress inducing pesticides, where highly exposed carriers of both risk genotypes were at the highest risk of PD (OR = 2.21, 95% CI [1.25, 3.86]); similar interactions were estimated for mitochondrial-inhibiting pesticides and paraquat alone. Additionally, paraquat exposure was found to impair mitochondrial respiration and increase mtDNA damage in in vivo and in vitro systems. Our findings provide insight into possible mechanisms involved in increased PD risk due to pesticide exposure in the context of BER genotype variants.

Association of Leukotrichia in Vitiligo and Asp148Glu Polymorphism of Apurinic/Apyrimidinic Endonuclease 1.

Background:Oxidative stress and increased DNA damage have been implicated in the etiopathogenesis of vitiligo. Oxidative DNA damage is mainly repaired by the base excision repair (BER) pathway.Aim:We sought to determine whether polymorphisms in DNA repair genes may have a role in the pathogenesis of vitiligo.Materials and Methods:We conducted a study including 100 patients with vitiligo and age- and sex-matched 193 control subjects to examine the role of single-nucleotide polymorphisms of BER genes, human 8-oxoG DNA N-glycosylase 1 (codon 326), apurinic/apyrimidinic endonuclease 1 (APE1) (codon 148), and X-ray repair cross-complementing group 1 (codon 399) as risk factors for vitiligo. These polymorphisms were determined by quantitative real-time polymerase chain reaction and melting curve analysis.Results:No significant association was observed between the variant alleles of studied genes and vitiligo.Conclusion:However, we showed that the presence of APE1 148Glu variant allele is associated with leukotrichia. This preliminary study suggests that APE1 (codon 148) polymorphism may play a role in vitiligo pathogenesis.

Base Excision Repair Gene OGG1 Affects the Relapse Risk of Acute Myeloid Leukemia

Background: Approximately 80% of acute myeloid leukemia (AML) patients can achieve complete remission, but around half of them relapse within five years. Recent studies have shown that AML relapse is associated with additional genetic mutation calls gclonal evolutionh in leukemic cell population (Ding, et al. Nature. 2012 & Parkin B, et al. Blood. 2013). These studies suggested that cytotoxic chemotherapy damaged cellular DNA and caused genetic mutation. In fact, anthracycline can produce 8-oxoguanine (8-OG) through induction of oxidative stress. 8-OG is most common DNA damage, which cause G:C to T:A transversion mutation. It is reported that transversion mutation more frequently observed in relapsed AML than primary AML. Base excision repair (BER) plays important role to correct base lesion including 8-OG and suppress genetic mutation. Therefore, we hypothesized BER gene polymorphisms may affect the risk of AML relapse, and focused five major functional polymorphisms: OGG1 S326C, MUTYH Q324H, APE1 D148E, XRCC1 R194W and XRCC1 R399Q.Material & Method: Ninety-four consecutive adults with AML who had achieved their first complete remission were recruited (male: 52, female: 42, age: 15-83 years, median age: 55.7 years). To remove the bias of the group, we also evaluated the risk in patients of non-M3 and under 65 years old (male: 22, female: 19, age: 15-64 years, median age: 49.0 years) (trimming group). These patients treated on Japan Adult Leukemia Study Group (JALSG) treatment protocols consisted of daunorubicin or idarubicin plus cytarabine (JALSG AML95, AML97, AML201, AML209). Genotyping was performed by PCR-RFLP method. The X2-test was used to compare the distribution of genotype and allele frequencies in patients. Leukemia-free survival (LFS) was calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test. In multivariate analysis, a stepwise selection procedure was performed using the proportional hazards Cox model for LFS. The variables were chosen with reference to previous studies; age, sex, white blood cell count and lactate dehydrogenase at diagnosis, number of induction courses, stem cell transplantation, MRC classification and history of tumor. This study was approved by the Institutional Review Board of Gunma University Hospital.Results: The OGG1 S326C CC genotype was observed significantly more often in the relapsed group (28.9% vs. 8.9%, OR = 4.10, 95% CI = 1.35-12.70, p = 0.01). In trimming group, the CC genotype was also observed more frequently in the relapsed group (50.0% vs. 6.9%, OR = 13.5, 95% CI = 2.17-84.0, p = 0.002). In addition, the OGG1 S326C CC genotype experienced a shorter median LFS than those with a non-CC genotype (CC vs. non-CC = 27.0 months vs. not reached, p = 0.02) (Figure 1). This genotype was also associated with poor LFS in trimming group (CC vs. non-CC = 11.0 months vs. not reached, p < 0.001) (Figure 1). Furthermore, multivariate analysis of LFS revealed OGG1 S326C CC genotype as an independent prognostic factor (HR = 4.32, 95% CI = 1.70-11.0, p = 0.002), like age, number of induction courses, and MRC classification (Table 1). Other polymorphisms had no significant effect on the risk of relapse.Conclusion: We previously reported that mutations by 8-OG were more efficiently suppressed in OGG1-S326 transduced cells than in OGG1-C326 transduced cells. Therefore, we hypothesized that low OGG1 activity promotes relapse of AML. To the best of our knowledge, this is the first report to show an association between BER gene polymorphisms and the relapse of AML. Our data suggest that OGG1 S326C can be a prognostic factor for AML relapse. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Association between Single-Nucleotide Polymorphisms of the hOGG1,NEIL1,APEX1, FEN1,LIG1, and LIG3 Genes and Alzheimer's Disease Risk

Background: One of the factors that contribute to Alzheimer's disease (AD) is the DNA damage caused by oxidative stress and inflammation that occurs in nerve cells. It has been suggested that the risk of AD may be associated with an age-dependent reduction of the DNA repair efficiency. Base excision repair (BER) is, among other things, a main repair system of oxidative DNA damage. One of the reasons for the reduced efficiency of this system may be single-nucleotide polymorphisms (SNP) of the genes encoding its proteins. Methods: DNA for genotyping was obtained from the peripheral blood of 281 patients and 150 controls. In the present study, we evaluated the impact of 8 polymorphisms of 6 BER genes on the AD risk. We analyzed the following SNP: c.-468T>G and c.444T>G of APEX1, c.*50C>T and c.*83A>C of LIG3, c.977C>G of OGG1, c.*283C>G of NEIL1, c.-441G>A of FEN1, and c.-7C>T of LIG1. Results: We showed that the LIG1 c.-7C>T A/A and LIG3 c.*83A>C A/C variants increased, while the APEX1 c.444T>G G/T, LIG1 c.-7C>T G/, LIG3 c.*83A>C C/C variants reduced, the AD risk. We also evaluated the relation between gene-gene interactions and the AD risk. We showed that combinations of certain BER gene variants such as c.977C>G×c.*50C>T CC/CT, c.444T>G×c.*50C>T GG/CT, c.-468T>G×c.*50C>T GG/CT, c.-441G>Ac.*50C>T×c.*50C>T GG/CT, c.*83A>C× c.*50C>T CT/AC, and c.-7C>T×c.*50C>T CT/GG can substantially positively modulate the risk of AD. Conclusions: In conclusion, we revealed that polymorphisms of BER genes may have a significant effect on the AD risk, and the presence of polymorphic variants may be an important marker for AD.

Variants of Base Excision Repair Genes MUTYH, PARP1 and XRCC1 in Alzheimer's Disease Risk

Background: Many clinical studies have shown that oxidative stress pathways and the efficiency of the oxidative DNA damage base excision repair (BER) system are associated with the pathogenesis of Alzheimer's disease (AD). Reduced BER efficiency may result from polymorphisms of BER-related genes. In the present study, we examine whether single nucleotide polymorphisms (SNPs) of BER genes are associated with increased risk of AD. Methods: SNP genotyping was carried out on DNA isolated from peripheral blood mononuclear cells obtained from 120 patients with AD and 110 healthy volunteers. Samples were genotyped for the presence of BER-related SNPs, i.e. XRCC1-rs1799782, rs25487; MUTYH-rs3219489, and PARP1-rs1136410. Results: We found a positive association between AD risk and the presence of G/A genotype variant of the XRCC1 rs25487 polymorphism [odds ratio (OR) = 3.762, 95% CI: 1.793-7.891]. The presence of the A/A genotype of this polymorphism reduced the risk of AD (OR = 0.485, 95% CI: 0.271-0.870). In cases of the PARP1 gene rs1136410 polymorphism, we observed that the T/C variant increases (OR = 4.159, 95% CI: 1.978-8.745) while the T/T variant reduces risk (OR = 0.240, 95% CI: 0.114-0.556) of AD. Conclusions: We conclude that BER gene polymorphisms may play an important role in the etiology of AD. Diagnosing the presence or absence of particular genetic variants may be an important marker of AD. Further research on a larger population is needed. There is also a need to examine polymorphisms of other BER in the context of AD risk.

Analysis of oxidative DNA damage and its repair in Polish patients with diabetes mellitus type 2: Role in pathogenesis of diabetic neuropathy

PurposeDistal symmetric polyneuropathy (DSPN) is common complication of type 2 diabetes (T2DM). In this work we investigated the role of oxidative damage in connection with particular polymorphisms of DNA repair genes and their repair capacity. Material/methodsMaterials constitute the peripheral blood of patients with T2DM with and without DSPN and control subjects without disturbance of the carbohydrate fraction. The study of gene polymorphisms which products take part in base excision repair (BER) pathway: 726 Val/Ala adenosine diphosphate ribosyl transferase (ADPRT), 324 His/Glu MutYhomolog (MUTYH) and 148 Asp/Glu human apurinic/apyrimidinic endonuclease (APE) was carried out using restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method. The study of DNA damage induced by hydrogen peroxide and the efficiency of their repair was carried out using comet assay. ResultsNone of the 3 polymorphisms were associated with the risk of DSPN. However, in group of patients together with T2DM and T2DM/DSPN 726 Ala ADPRT allele was significantly susceptible to increased risk of T2DM (OR=1.59; 95% CI: 1.08–2.36). Investigation of DNA damage and repair revealed that T2DM patients have decreased ability to DNA repair. This capacity even drops down in the group of T2DM/DSPN patients compared to subjects with diabetes alone. ADPRT and APE polymorphisms were significantly associated with higher DNA damages (P<0.05) in heterozygous and mutant homozygous in correlation to homozygous wild type, but for MUTYH polymorphism relation was not confirmed. ConclusionsPathogenesis of T2DM and development of DSPN may be related to oxidative stress connected with BER gene polymorphisms.

XRCC1 rs25487 polymorphism is associated with lung cancer risk in epidemiologically susceptible Chinese people.

Base excision repair (BER) plays an important role in maintaining genome integrity and anti-cancer drug resistance. Single nu-cleotide polymorphisms (SNPs) in BER genes were detected in 500 lung cancer patients and 500 cancer-free controls. A logistic regression model was applied to analyze the relationship between lung cancer susceptibility and BER SNPs coupled with a wide range of epidemiological factors in a Chinese population. SNPs including rs25487 in the X-ray repair cross-complementing group 1 gene, rs1052133 in the 8-oxoguanine DNA gly-cosylase gene, and rs1136410 in the poly (ADP-ribose) polymerase 1 gene were identified. Multivariate analysis showed that the rs25487-AG geno-type was associated with a higher incidence of lung cancer compared with the GG genotype. The rs25487 SNP was associated with the pathological distribution of lung cancer. Moreover, rs1052133-GG was associated with early age of lung cancer onset compared with the CC genotype. Our data demonstrated that the SNPs rs25487 and rs1052133 are risk factors for lung cancer in epidemiologically susceptible Chinese people.

Gene–environment interaction involved in cholangiocarcinoma in the Thai population: polymorphisms of DNA repair genes, smoking and use of alcohol

ObjectiveCholangiocarcinoma (CCA) is the most common malignancy in a Northeast Thai population. Smoking and alcohol drinking are associated with the production of free radical intermediates, which can cause several types...

Single Nucleotide Polymorphisms of DNA Base-excision Repair Genes (APE1, OGG1 and XRCC1) Associated with Breast Cancer Risk in a Chinese Population

Altered DNA repair capacity can result in increased susceptibility to cancer. The base excision repair (BER) pathway effectively removes DNA damage caused by ionizing radiation and reactive oxidative species (ROS). In the current study, we analyzed the possible relation of polymorphisms in BER genes, including 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease 1 (APE1), and X-ray repair cross-complementing group 1 protein (XRCC1), with breast cancer risk in Chinese Han women. This case-control study examined 194 patients with breast cancer and 245 cancer-free hospitalized control subjects. Single nucleotide polymorphisms (SNPs) of OGG1 (Ser326Cys), XRCC1 (Arg399Gln), and APE1 (Asp148Glu and -141T/G) were genotyped and analyzed for their association with breast cancer risk using multivariate logistic regression models. We found that XRCC1 Arg399Gln was significantly associated with an increased risk of breast cancer. Similarly, the XRCC1 Gln allele was significantly associated with an elevated risk in postmenopausal women and women with a high BMI (≥ 24 kg/m2). The OGG1 Cys allele provided a significant protective effect against developing cancer in women with a low BMI (< 24 kg/m2). When analyzing the combined effects of these alleles on the risk of breast cancer, we found that individuals with ≥ 2 adverse genotypes (XRCC1 399Gln, APE1 148Asp, and OGG1 326Ser) were at a 2.18-fold increased risk of breast cancer (P = 0.027). In conclusion, our data indicate that Chinese women with the 399Gln allele of XRCC1 have an increased risk of breast cancer, and the combined effects of polymorphisms of BER genes may contribute to tumorigenesis.